To initiate an effective infection microbial pathogens utilize a variety of their surface components to bind to extracellular matrix (ECM) proteins. ECM proteins such as fibronectin, vitronectin, thrombospondin and collagens have been shown to serve as docking sites for microbial pathogens to establish colonization in tissues. Our studies show that Mindin, an ECM protein, plays a critical role in the innate immune response. Mindin belongs to the F-spondin family and is highly conserved across species. Mindin deficient mice are resistant to lipopolysaccharide (LPS) induced septic shock and produced low levels of inflammatory cytokines upon LPS challenge. Strikingly, macrophages from Mindin deficient mice exhibit severely defective in vitro responses to stimuli from Gram-positive, Gram-negative bacteria and yeast. Moreover, Mindin binds to LPS directly. These results demonstrate a key role of Mindin in the initiation of the innate immune response and suggest that Mindin is required for the recognition of a broad spectrum of pathogens by macrophages. Our data suggest that Mindin may play multiple roles in the innate immune response. On one hand, Mindin may directly bind to microbial pathogens in tissues. On the other hand, Mindin may participate as an integral part of pattern recognition receptors (PRRs) on macrophages to detect microbial pathogens. In this proposal, we will determine the structural basis by which Mindin interacts with LPS. We will examine whether Mindin participates as an integral part of some of the currently identified PRRs. The role of Mindin in host defense against microbial infection will be examined using Mindin / mice as in vivo model system. Finally, we will test whether in vivo disruption of the interaction between Mindin and LPS or Mindin and its putative receptors will improve the outcome of LPS-induced septic shock. Results from this proposal will provide novel insights on the mechanisms of the innate immune response and may have implication for clinical treatment of septic shock and other microbe caused diseases. [unreadable] [unreadable]